This invention relates to compounds with combined bradykinin and neurokinin receptor antagonist activity and to methods of using the same.
Neurokinins (tachykinins) are a group of naturally occurring peptides found in a variety of human and mammalian tissues. Neurokinins are believed to be involved in a large number of physiological processes within the digestive, circulatory, pulmonary, central nervous and peripheral nervous systems. Substance P, a member of the neurokinin group, is believed to be involved in the neurotransmission of pain sensations [TIPS 8 506 (1987)] and has been implicated as playing an important role in pain or neurogenic inflammation in a number of disease states including migraine [D. Regoli in "Trends in Cluster Headache", Elsevier, p. 85, (1987) and B. Sandberg et al, J. Med. Chem. 25 1009 (1982)], arthritis [Gronblad et al, J. Rheumatol. 15 1807 (1988)], and inflammatory bowel disease [Mantyh et al, Neuroscience 25 817 (1988)].
Substance P is stored in primary sensory C-fibers, while in the airway, it is found in nonmyelinated afferent C-fibers. Stimulation of these nerve fibers by the action of bradykinin, antigens, capsaicin, chemical or mechanical irritation, can cause the release of substance P [C. R. Martling et al, Life Sciences 40 1633 (1987)] stimulating a number of airway inflammatory responses including edema formation, mucus secretion, inflammatory cell infiltration and cough. [J. A. Lowe in Annual reports in Medicinal Chemistry 28 99 (1993)]. Substance P has been implicated in the pathophysiology of several airway disorders including bronchitis and asthma.
The NK.sub.1 receptor (the neurokinin receptor with the highest specificity for substance P) has extensive pulmonary distribution and is found on both epithelial cells and endothelial cells, as well as on several types of circulating leukocytes. NK.sub.1 receptor antagonist capable of blocking this receptor would have broad application in treating or eliminating a large number of disease states such as those described above. In addition, neurokinin receptor antagonists may be useful in treating demyelinating disorders such as multiple sclerosis and amyotrophic lateral sclerosis.
A large number of both peptide and nonpeptide neurokinin type 1 (NK.sub.1) receptor antagonists are known. Recently, it has been demonstrated that several non-peptide NK.sub.1 antagonists exhibit nonspecific action and interact with calcium channels or exhibit unusual non-competitive antagonist action on NK.sub.1 receptors in isolated tissues. Fujisawa has reported two peptide based antagonists, FR113680 and FK888. Although both of these compounds are specific NK.sub.1 antagonists, FR113680 lacks sufficient potency, stability, and solubility to be a viable pharmaceutical agent [Hagiwara, D. et al, J. Med Chem. 35:3184 (1992)]. FK888, although more potent than FR113680, does not approach the potency of Pfizer CP-99994 (Desai, M. C. et al, J. Med. Chem. 35:4911-4913 (1993)), which is reported to be 10 times more potent than FK888 in binding studies. In addition, FK888 also has poor water solubility characteristics, a factor that limits its application as an inhaled, injected or intravenously administered drug.
FR113680 is a species generically represented by the formula: R.sup.1 -A-D-Trp-Phe(NR.sup.2)-R.sup.3, where R.sup.1 is hydrogen or an amino protective group; A is one or two amino acid residues, and R.sup.2 is lower alkyl and R.sup.3 is alkylaromatic. Although a number of suitable protective groups for R.sup.1 have been defined, succinimido-alkanylcarboxylates, or peptides attached to such structures have not been described. (See, for example, European Patent Application (EPA) 89104617.9)
Patent applications related to EPA 89104617.9, such as EP patent application 90107822.0, U.S. Pat. No. 5,164,372, and WO 92JP780 describe structures of the general formula: ##STR1## wherein A is an amino acid with "suitable substituents." Although lysine is mentioned in these documents succinimido-alkanylcarboxylates, or peptides attached through such structures are not described as suitable substituents for A. In publications related to the disclosure of FK-888 (such as EP 90123875) A in the above general formula is defined specifically as proline or a closely related structure. Publications dealing with these classes of compounds specifically dissuade one skilled in the art from making substitutions or additions at A. For example, FR113680 was shown to have a binding constant of 5.8.times.10.sup.-9 Molar on isolated guinea pig lung membrane [Hagiwara et al, J. Med Chem. 35 3148 (1992)], while analogs incorporating Lys at position A, were all at least 10 fold less potent than this parent compound, and substituents on this Lys residue at the .alpha.-amino nitrogen produced compounds of lesser or equal potency than FR113680. [Hagiwara et al, J. Med. Chem 36 2266 (1993)]. Compounds such as compound CP-0533, described herein, which was reported by Fujisawa, showed, in the absence of organic solvents, minimal water solubility and gave poor assay results.
Bradykinin (BK) is an endogenous peptide hormone released by proteolytic cleavage of kininogen by a group of endopeptidases known as kallikreins. Bradykinins are mediators in eliciting many pathophysiological responses including pain and hyperalgesia via stimulation of peripheral A- and C-fiber neurons [Farmer, S. G. in Bradykinin Antagonists, R. M. Burch, ed., Marcel Dekker, Inc. New York, pp. 1-31, (1991); Griesbacher, T., Br. J. Pharmacol., 92:333-340 (1987); Taiwo, Y. O., Brain Res., 458:402-406 (1988); Steranka, I. R. et al, Proc. Nat. Acad. Sci. USA, 85:3245-3249 (1988); Dray, A., Neurosci. Lett., 91:301-307 (1988); Sterankan, L. R., FASEB J., 3:2019-2025 (1989); Neurosci. Lett., 97:198-202 (1989)].
In addition, there is evidence that BK plays an important role in inflammatory response [Marceau, F., Gen. Pharmacol., 14:209-229 (1983); Proud, D., Annu. Rev. Immunol., 6:49-84 (1988); Colman, R. W. in Bradykinin, Kallidin and Kallikrein, Handbook of Experimental Pharmacology, Vol. 25, Erdos, E. G. ed., Springer Verlag, New York (1979); Greaves, M. W., Br. J. Dermatol., 119:419-426 (1988)] and is a significant mediator in several disease states including hypotension associated with sepsis, [Thrombosis and Haemostasis, 58:709-719 (1978); Whalley, E. T., Agents and Actions, 38:413-420 (1992)] and bronchopulmonary disorders including asthma [Farmer, S. G. in Bradykinin Antagonists, R. M. Burch, ed., Marcel Dekker, Inc., New York, pp. 213-236 and 261-276 (1991)]. There is also compelling evidence that bradykinin receptor antagonists may be useful in the treatment of edema (swelling) in head trauma, [Unterberg, A., J. Neurosurgery, 64:269-276 (1986)] edema and pain from severe burns, [Holder, I. A., Journal of Burn Care and Rehabilitation, 11:496503 (1990).], migraine pain, [Sicuteri, F., Res. Clin. Stud. Headache, 1:6 (1967)] and pain associated with surgical procedures or cancer. Recent animal studies also indicate that bradykinin receptor antagonists may be extremely efficacious in prolonging survival in cases of severe general trauma [Christopher, T. A. et al., Am. J. Physiol. 226:H867-H873 (1994)]. Notwithstanding prior efforts, there remains a considerable need to provide improved BK and NK.sub.1 antagonists with useful receptor antagonist and pharmaco-kinetic properties. The main object of the present invention is to provide such receptor antagonists which include BK-NK.sub.1 antagonist heterodimers demonstrating superior synergistic action, improved activity and increased solubility under physiological conditions.